1. Field of the Invention
Cardiac arrhythmias are disorders of impulse generation that result fro disruptions of normal cardiac pacemaker activity, from disturbances in cardiac conductive fibers, or from a combination of both preceding factors. Cardiac arrhythmias of clinical significance in man include: premature contractions (extrasystoles) originating in atrial or ventricular foci; paroxysmal supraventricular tachycardia; atrial flutter; atrial fibrillation; ventricular tachycardia; and ventricular fibrillation. Arrhythmias can be induced in laboratory animals that are suitable experimental models of man to study physiological mechanisms of the disorder or to screen new antiarrhythmic agents.
Clinical treatment of arrhythmias includes administration of a variety of drugs, although quinidine, procainamide, and diphenylhydantoin are current mainstays.
Quinidine is the d-isomer of quinine: ##STR2## while procainamide is p-amino-N-(2-diethylaminoethyl)benzamide: ##STR3## I and II require extreme care in administration because they are relatively toxic. In weighing their efficacy over their toxicity, however, the former is countervailing. Because of limitations in those antiarrhythmic drugs, there have been efforts to discover safer substitutes. The discovery of the antiarrhythmic activity of diphenylhydantoin opened new approaches in the design of new compounds exhibiting such activity.
Diphenylhydantoin (5,5-diphenyl-2,4-imidazolidinedione; "DPH"), ##STR4## initially was utilized in the treatment of epilepsy but later was discovered to have important antiarrhythmic applications. The pharmacodynamics of DPH differ from those of quinidine and of procainamide, and DPH does not exhibit the toxic properties of either drug. DPH specifically antagonizes ventricular arrhythmias induced by digitalis, depresses ventricular automaticity, enhances atrio-ventricular modal conduction, and reduces the effective refractory period. DPH, however, is not without untoward side effects: dizziness, nausea, emesis, nystimus, and ataxia. Large doses of DPH may produce atrio-ventricular blockage, bradycardia, or even cardiac arrest. For a review of the current status of the field and of DPH as an antiarrhythmic agent, see: G. K. Moe and J. A. Albildskow, "Antiarrhytmic Drugs", in: The Pharmacological Basis of Therpeutics, 4th Edition, L. S. Goodman and A. Gilman, Editors, MacMillan Company, New York, Chapter 32 (1970); and L. S. Dreifus and Y. Watanabe, Amer. Heart J., 80: 709-713 (1970).